Within the pharmaceutical industry there is an increasing interest in providing products of a higher quality. Streamlining of a process line by including probes or sensors capable of in-line or on-line analysis may provide increased product quality and process efficiency, by making it possible to obtain analytical results before and after each step allowing each unit operation to be controlled on the basis of these results. In addition, still stricter requirements to process reproducibility and safety are to be expected from authorities granting marketing authorisations. Recent ideas behind how pharmaceutical processes should be designed and performed have been formulated as a set of guidelines by the Food and Drug Administration (FDA) in the USA. The FDA uses the term “Process Analytical Technology” (PAT), and in their Guidance for Industry regarding PAT (dated September 2004), it is stated that “the Agency considers PAT to be a system for designing, analysing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality. It is important to note that the term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner. The goal of PAT is to enhance understanding and control the manufacturing process, which is consistent with our current drug quality system: quality cannot be tested into products; it should be built-in or should be by design. Consequently, the tools and principles described in this guidance should be used for gaining process understanding and can also be used to meet the regulatory requirements for validating and controlling the manufacturing process.” An example of a virtual platform to facilitate automated production is given in US2005/0137735, wherein a plan for handling information streams and applying the information in a process design is suggested.
In addition to improving the processing efficiency there is a general interest in providing processes that are both environmentally safer and also pose a reduced risk to an operator of the process. In particular, in a process to produce tablets from active pharmaceutical ingredients (API) and various excipients in a powdery form may require the operator to wear a protective breathing apparatus, or otherwise personal protective equipment, like gloves or coverall, to prevent excessive exposure to the API and also the excipients. Reduction of the risk of contamination of the surrounding environment as well as exposure of the operator to a pharmaceutical product in a tabletting process was addressed in WO03/020499 (Courtoy), wherein a rotary tablet press was described.
However, WO03/020499 does not take into account the interest in providing better process control as it is described in the PAT guidelines of the FDA.
Typical manufacturing processes employed within the pharmaceutical field until now are of a batch nature. Batch manufacturing processes have a number of advantages and provide satisfactory results within many areas. However, due the increasingly widespread application of PAT criteria for monitoring and controlling in particular pharmaceutical manufacturing processes, and to the general increase in the demands to quality by design, the level of quality of monitoring and control attainable by a batch process is often not sufficient, i.a. due to the fact that settings are fixed. Furthermore, a relatively large buffer volume is required, entailing undesired back-mixing of the material stream and a limited traceability of the manufactured product. As a consequence, manufacturers' and customers' focus of interest has shifted to continuous processes, in which settings may be varied and are allowed to change within a design space. In order to achieve more production output with a batch process, bigger equipment and bigger buffer volumes, with different process settings to attain the same output, would be required. This is known as the scale-up problem. More output with a continuous process just requires longer running, with the ability to maintain the same settings. Further advantages of the continuous process include the ability to provide real-time release and its inherent advantages: Less product in stock, less quality testing, faster time-to-market, less costs involved etc. Furthermore, there is an increased interest for more robust processing equipment and for the ability to control more incoming variation, while maintaining tablet quality.
One example of a continuous process for producing tablets is described in EP 0 275 834 A1, in which two or more ingredients are fed into the process line at various feed or inlet points, and the ingredients are mixed, dried and subsequently compacted in a conventional tabletting machine. The process line includes a first mixing unit, a drying unit, a sizing unit and a second mixing unit.
Ideally, the output from the tabletting machine corresponds to the aggregated input of ingredients at the feed or inlet points, i.e. all of the material is fed to the tabletting machine in a continuous flow and at a constant rate. Due to a variety of factors, this is not feasible in practice. First, it is under any circumstances almost impossible to adjust the output from the mixing and drying units to provide a just-in-time supply of material to the tabletting machine. Second, the continuous production of tablets of a desired high level of quality requires careful monitoring, controlling and adjustment of process parameters in order to avoid a large rejection number from the tabletting machine. This may lead to accumulation of material along the process line awaiting adjustment of certain process parameters. In turn, this inevitably necessitates the use of intermediate buffer vessels in order to store material upstream of the tablet press.